Figure S1 Study selection process for literature review.1

2

3

Appendix

Members of GAMES:

Hospital Costa del Sol, (Marbella): Fernando Fernández Sánchez, Mariam Noureddine,

Gabriel Rosas, Javier de la Torre Lima; Hospital Universitario de Cruces, (Bilbao):

José Aramendi, Elena Bereciartua, María Victoria Boado, Marta Campaña Lázaro,

Josune Goikoetxea, Juan José Goiti, José Luis Hernández, José Ramón Iruretagoyena,

Josu Irurzun Zuazabal, Leire López-Soria, Miguel Montejo, Pedro María Pérez, Regino

Rodríguez, Roberto Voces; Hospital Universitario Virgen de la Victoria, (Málaga):

Mª Victoria García López, Radka Ivanova Georgieva, Manuel Márquez Solero, Isabel

Rodríguez Bailón, Josefa Ruiz Morales; Hospital Universitario Donostia-Policlínica

Gipuzkoa, (San Sebastián): Ana María Cuende, Tomás Echeverría, Ana Fuerte,

Eduardo Gaminde, Miguel Ángel Goenaga, Pedro Idígoras, José Antonio Iribarren,

Alberto Izaguirre Yarza, Carlos Reviejo; Hospital General Universitario de Alicante,

(Alicante): Rafael Carrasco, Vicente Climent, Patricio Llamas, Esperanza Merino,

Joaquín Plazas, Sergio Reus; Complejo Hospitalario Universitario A Coruña, (A

Coruña): Nemesio Álvarez, José María Bravo-Ferrer, María del Mar Carmona, Laura

Castelo, José Cuenca, Pedro Llinares, Enrique Miguez Rey, María Rodríguez Mayo,

Dolores Sousa, Mª Carmen Zúñiga; Complejo Hospitalario de Especialidades Juan

Ramón Jiménez, (Huelva): Francisco Javier Martínez; Hospital Universitario de

Canarias, (Canarias): Mª del Mar Alonso, Beatriz Castro, Dácil García Marrero, Mª del

Carmen Durán, Mª Antonia Miguel Gómez, Juan La Calzada, Ibrahim Nassar; Hospital

Regional Universitario Carlos Haya, (Málaga): Antonio Plata Ciezar, José Mª

Reguera Iglesias; Hospital Universitario Central Asturias, (Oviedo): Víctor Asensi

Álvarez, Carlos Costas, Jesús de la Hera, Jonnathan Fernández Suárez, Lisardo Iglesias

Fraile, Víctor León Arguero, José López Menéndez, Pilar Mencia Bajo, Carlos Morales,

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Alfonso Moreno Torrico, Carmen Palomo, Begoña Paya Martínez, Ángeles Rodríguez

Esteban, Raquel Rodríguez García, Mauricio Telenti Asensio; Hospital Universitario

Clínic de Barcelona, (Barcelona): Manuel Almela, Yolanda Armero, Manuel Azqueta,

Mercé Brunet, Ramón Cartañá, Carlos Cervera, Carlos Falces, Guillermina Fita, David

Fuster, Cristina García de la Maria, José M. Gatell, Jaume Llopis Pérez, Francesc

Marco, Carlos A. Mestres, José Mª Miró, Asunción Moreno, Salvador Ninot, Eduardo

Quintana, , Carlos Paré, Juan Manuel Pericás, José L. Pomar, José Ramírez, Irene

Rovira, Marta Sitges, Dolors Soy, Adrián Téllez, Jordi Vila; Hospital General

Universitario Gregorio Marañón, (Madrid): Javier Bermejo, Emilio Bouza, Gregorio

Cuerpo, Viviana de Egea, Alia Eworo, Ana Fernández Cruz, Mª Eugenia García Leoni,

Marcela González del Vecchio, Víctor González Ramallo, Martha Kestler Hernández,

Mercedes Marín, Manuel Martínez-Sellés, Mª Cruz Menárguez, Patricia Muñoz,

Cristina Rincón, Hugo Rodríguez-Abella, Marta Rodríguez-Créixems, Blanca Pinilla,

Ángel Pinto, Maricela Valerio, Eduardo Verde Moreno; Hospital Universitario La

Paz, (Madrid): Isabel Antorrena, Mar Moreno, José Ramón Paño, Sandra Rosillo, María

Romero, Araceli Saldaña; Hospital Universitario Marqués de Valdecilla,

(Santander): Carlos Armiñanzas Castillo, Ana Arnaiz, José Berrazueta, Sara Bellisco,

Manuel Cobo Belaustegui, Raquel Durán, MªCarmen Fariñas, Concepción Fariñas-

Álvarez, Carlos Fernández Mazarrasa, Rubén Gómez Izquierdo, Claudia González

Rico, José Gutiérrez Díez, Rafael Martín Durán, Marcos Pajarón, José Antonio Parra,

Ramón Teira, Jesús Zarauza; Hospital Universitario Puerta de Hierro, (Madrid):

Pablo García-Pavía, Jesús G. Mirelis, Beatriz Orden, Antonio Ramos, Isabel Sanchez,

Fernando Dominguez, Carlos Garcia-Montero, Luis Alonso-Pulpón; Hospital

Universitario Ramón y Cajal, (Madrid): Tomasa Centella, José Manuel Hermida, José

Luis Moya, Pilar Martín-Dávila, Enrique Navas, Enrique Oliva, Alejandro del Río,

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Soledad Ruiz; Hospital Universitario Virgen de las Nieves, (Granada): Carmen

Hidalgo Tenorio; Hospital Universitario Virgen Macarena, (Sevilla): Antonio de

Castro, Marina de Cueto, Pastora Gallego, Juan Gálvez Acebal, Jesús Rodríguez Baño;

Hospital Universitario Virgen del Rocío, (Sevilla): Arístides de Alarcón, Emilio

García, Juan Luis Haro, José Antonio Lepe, Francisco López, Rafael Luque; Hospital

San Pedro, (Logroño): Luis Javier Alonso, José Manuel Azcona Gutiérrez, José Ramón

Blanco, Lara García, José Antonio Oteo; Hospital de la Santa Creu i Sant Pau,

(Barcelona): Natividad de Benito, Mercé Gurguí, Cristina Pacho, Roser Pericas,

Guillem Pons; Complejo Hospitalario Universitario de Santiago de Compostela, (A

Coruña): M. Álvarez, A. L. Fernández, Amparo Martínez, A. Prieto, Benito Regueiro,

E. Tijeira, Marino Vega; Hospital Santiago Apóstol, (Vitoria): Andrés Canut Blasco,

José Cordo Mollar, Juan Carlos Gainzarain Arana, Oscar García Uriarte, Alejandro

Martín López, Zuriñe Ortiz de Zárate, José Antonio Urturi Matos; Hospital SAS Línea

de la Concepción, (Cádiz): Mª Belén Nacle, Antonio Sánchez, Luis Vallejo; Hospital

Clínico Universitario Virgen de la Arrixaca (Murcia): José Mª Arribas Leal, Elisa

García Vázquez, Alicia Hernández Torres, Ana Blázquez, Gonzalo de la Morena

Valenzuela; Hospital de Txagorritxu, (Vitoria): Ángel Alonso, Javier Aramburu,

Felicitas Elena Calvo, Anai Moreno Rodríguez, Paola Tarabini-Castellani; Hospital

Virgen de la Salud, (Toledo): Eva Heredero Gálvez, Carolina Maicas Bellido, Mª

Antonia Sepúlveda; Hospital Rafael Méndez, (Lorca-Murcia): Eva Cascales Alcolea,

Pilar Egea Serrano, José Joaquín Hernández Roca.

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Table S1: Baseline characteristics of the total study population (n=2011).

Variable N= 2011Patient age, IQR (years) 69 (57 - 76)Male sex, n (%) 1368 (68)ComorbiditiesAge adjusted Charlson comorbidity score, mean (SD)

4.58 (2.6)

Chronic renal impairment, n (%) 508 (25.2) Diabetes mellitus, n (%) 544 (27.1) Cancer, n (%) 314 (15.6) Neurological disease, n (%) 131 (6.5)Predisposing conditions, n (%) Pre-existing valve disease 870 (43.3) Congenital cardiac disease 111 (5.5) Previous endocarditis 162 (8.1) Intravenous drug abuse 55 (2.7)Echocardiography performed, n (%) TTE 1863 (92.6) TEE 1531 (76.1)Site of infection, n (%) Aortic 952 (47.3) Mitral 894 (44.5) Pulmonary 29 (1.4) Tricuspid 114 (5.7) Native 1277 (63.5) Prosthetic 571 (28.4)

IQR: Interquartile range; SD: Standard deviation; TTE: Transthoracic echocardiogram; TEE: Transesophageal echocardiography

78

79

808182

Table S2: Clinical, microbiological and echocardiographic characteristics of HCM patients complicated by IE according to English and Spanish language case reports published between 1961 and 2014 (n=84).

N Age Gender NYHA Wall thickness Hypertrophy ASM LVOTO

Gradient Affected valve

Predisposing factor

Infective agent Surgery Death Year Author

1 37 F U U U U U U U Dental procedure

Streptococcus viridans U No 1961 Boiteau et al. (w1)

2 23 F U U U U U U Mitral Abortion Streptococcus viridans U No 1961 Boiteau et al. (w1)

3 29 M I U U U Yes 30 mmHg U U Streptococcus viridans No No 1966 Linhart et al. (w2)

4 34 M II 30 mm Concentric U Yes 40 mmHg Aortic Dermatitis Negative No Yes 1967 Nagle et al. (w3)

5 39 M I 39 mm Septal U Yes 127 mmHg Mitral U Negative No Yes 1968 Vecht et al. (w4)

6 49 F III U U U Yes 67 mmHg U U Streptococcus No Yes 1968 Vecht et al. (w4)

7 59 F II U U U No U U U Staphylococcus albus No No 1968 Vecht et al. (w4)

8 45 M II U U U Yes U Aortic Cardiac catheterization

Streptococcus viridans Yes No 1968 Frank et al. (w5)

9 61 F II U U U Yes U U U Streptococcus viridans Yes No 1968 Frank et al. (w5)

10 43 F II U U U Yes U U U U U No 1968 Frank et al. (w5)

11 20 F U U U U U U U Dental procedure

Streptococcus faecalis No 1969 Epstein et al. (w6)

12 39 M U U U U U U U Cardiac catheterization

Corynebacterium sp U No 1969 Epstein et al. (w6)

13 58 M I U U U No U U U Streptococcus viridans No No 1971 Cardelia et al. (w7)

14 40 F I U U U No 116 mmHg U Dental procedure

Streptococcus viridans No No 1975 Garrido Pintor et al. (w8)

15 43 M I 25 mm Concentric U Yes U Aortic and Mitral

U Enterococcus U Yes 1975 Wang et al. (w9)

16 34 M I U U U Yes 50 mmHg Mitral U Staphylococcus aureus Yes No 1977 Huret et al. (w10)

17 60 F I U U U U U U Dental procedure

Streptococcus mutans No No 1977 Robbins et (w11)

18 61 M II U U Yes U U U U Streptococcus mutans U No 1977 Robbins et al. (w11)

19 53 M II U U Yes U U U U Listeria monocytogenes No No 1978 Pitcher et al. (w12)

20 58 F I 22 mm Septal Yes Yes U Aortic and LVOT

U Streptococcus pneumoniae No Yes 1979 LeJemtel et al. (w13)

83848586

21 66 F I U U Yes Yes U Aortic, mital and LVOT

U Enterococcus Yes Yes 1979 LeJemtel et al. (w13)

22 64 F II U U U Yes 105 mmHg Aortic and Mitral

U Staphylococcus aureus Yes Yes 1979 Greenland et al. (w14)

23 63 F I 20 mm Septal Yes Yes U Mitral Varicose ulcer Staphylococcus aureus No Yes 1981 Bosch Gil et al. (w15)

24 53 F III 21 mm Septal Yes Yes 100 mmHg Aortic U Streptococcus viridans Yes Yes 1981 Mensa Pueyo et al. (w16)

25 45 M II U U Yes 90 mmHg U Miectomy Streptococcus viridans No No 1982 Chagnac et al. (w17)

26 40 M II U U Yes Yes U U U Streptococcus viridans No No 1982 Chagnac et al. (w17)

27 63 F I U U Yes Yes U U U Enterococcus No No 1982 Chagnac et al. (w17)

28 76 M II U U U Yes U Mitral U U No No 1982 Martinez Orozco et al. (w18)

29 38 M I U U U Yes U U U Actinobacillus Yes No 1983 Ah Fat et al. (w19)

30 57 M I 19 mm U Yes Yes 125 mmHg Mitral Dermatitis Streptococcus viridans No No 1983 Ovsyshcher et al. (w20)

31 61 M I U Septal U U U U IV catheterization

Staphylococcus epidermidis No Yes 1983 Bolivar et al. (w21)

32 52 M I U U U Yes U Mitral U Candida tropicalis Yes Yes 1984 Malouf et al. (w22)

33 70 M I U U U Yes 70 mmHg Mitral U Streptococcus viridans / Lactobacillus spp

Yes No 1989 Stulz et al. (w23)

34 51 M U 2.2 (IVS/PW) Septal U U U Mitral U Streptococcus faecalis Yes No 1990 Alessandri et al. (2)

35 76 M U 1.8 (IVS/PW) U Yes Yes 40 mmHg Aortic and Mitral

U Streptococcus coagulasa negativo

No No 1990 Alessandri et al. (2)

36 64 M U 2.8 (IVS/PW) Septal Yes Yes 80 mmHg Aortic and Mitral

Hemorroidectomy

Streptococcus viridans No No 1990 Alessandri et al. (2)

37 48 F U 2.2 (IVS/PW) Septal U Yes 45 mmHg Mitral U Streptococcus mitis No No 1990 Alessandri et al. (2)

38 56 F U 2.3(IVS/PW) Septal Yes Yes 30 mmHg Aortic and Mitral

U Brucella No No 1990 Alessandri et al. (2)

39 68 M U 1.8 (IVS/PW) Septal Yes Yes 30 mmHg Aórtica y Mitral

U Streptococcus faecalis Yes No 1990 Alessandri et al. (2)

40 67 F U 2.3 (IVS/PW) Septal Yes Yes 80 mmHg Mitral Sinovitis U No No 1990 Alessandri et al. (2)

41 22 F I 20 mm Concentric Yes Yes 71 mmHg Mitral U U Yes No 1991 Anguita et al. (w24)

42 11 F I 30 mm Septal Yes Yes 62 mmHg Aortic and Mitral

U Streptococcus sanguis No U 1992 Chen et al. (w25)

43 12 M II 20 mm Septal Yes Yes 62 mmHg Mitral U U Yes No 1992 Roberts et al. (w26)

44 25 M II U Septal U No U U U U U No 1992 Roberts et al. (w26)

45 43 M II 17 mm Septal Yes No 26 mmHg Mitral U U Yes No 1992 Roberts et al. (w26)

46 46 M U 29 mm Septal No Yes 45 mmHg Mitral Dental procedure

Cardiobacterium hominis Yes No 1992 Roberts et al. (w26)

47 63 M III 32 mm Septal Yes Yes 85 mmHg Mitral Dental procedure

U Yes No 1992 Roberts et al. (w26)

48 64 M II 26 mm Septal No No 5 mmHg Mitral Cardiac catheterization

Enterococcus Yes No 1992 Roberts et al. (w26)

49 71 M II U Septal Yes No U Mitral U Streptococcus (alpha hemolytic)

Yes Yes 1992 Roberts et al. (w26)

50 51 M I 20 mm Septal Yes No U Aortic U U Yes No 1992 Roberts et al. (w26)

51 52 F II 26 mm Septal No Yes 78 mmHg Aortic U U Yes No 1992 Roberts et al. (w26)

52 54 F I 24 mm Septal No Yes 70 mmHg Aortic Cardiac catheterization

Streptococcus (alpha hemolytic)

Yes No 1992 Roberts et al. (w26)

53 58 M II U Septal No Yes 140 mmHg Aortic and Mitral

IV drug abuse Streptococcus (alpha hemolytic)

Yes Yes 1992 Roberts et al. (w26)

54 29 F I U U U Yes U U Dental procedure

Gemella morbillorum Yes No 1994 Kerr et al. (w27)

55 30 M I U U Yes Yes U U U Neisseria elongata No No 1998 Hofstad et al. (w28)

56 52 M I 22 mm U U Yes U Mitral U U No No 1999 Spirito et al. (1)

57 23 M II 30 mm U U Yes U Mitral IV drug abuse U No Yes 1999 Spirito et al. (1)

58 26 M III 27 mm U U Yes U Mitral Dental procedure

Streptococcus sanguis Yes No 1999 Spirito et al. (1)

59 31 F IV 17 mm U U Yes U Aortic and Mitral

Dental procedure

Staphylococcus aureus Yes No 1999 Spirito et al. (1)

60 38 M III 26 mm U U Yes U Mitral Dental procedure

Enterococcus faecalis No No 1999 Spirito et al. (1)

61 49 M IV 20 mm U U Yes U Mitral Dental procedure

U Yes No 1999 Spirito et al. (1)

62 42 M II 26 mm U U Yes U Aortic and Mitral

U Staphylococcus epidermidis No No 1999 Spirito et al. (1)

63 48 F II 28 mm U U Yes U Mitral U Streprococcus viridans No No 1999 Spirito et al. (1)

64 16 M III 17 mm U U Yes U Aortic and Mitral

U Staphylococcus aureus Yes No 1999 Spirito et al. (1)

65 62 F II 26 mm U U Yes U Mitral U U No No 1999 Spirito et al. (1)

66 59 M U U Septal Yes Yes 50 mmHg Mitral U Staphylococcus epidermidis Yes No 2002 Decastro et al. (w29)

67 42 M U U U Yes Yes 65 mmHg Aortic and Mitral

Dental procedure

Staphylococcus epidermidis Yes No 2002 Decastro et al. (w29)

68 35 F U U U Yes Yes 80 mmHg Aortic U Staphylococcus aureus No Yes 2002 Decastro et al. (w29)69 27 M I 24 mm Septal Yes Yes 36 mmHg Mitral Dental

procedureStaphylococcus aureus Yes No 2002 Morgan-Hughes et al.

(w30)

70 29 M I U U Yes Yes 100 mmHg Mitral U Streptococcus viridans Yes U 2004 Inoue et al. (w31)

71 27 F I 21 mm Septal U No Apical septum

IV drug abuse Listeria monocytogenes No No 2006 Bosch et al. (w32)

72 46 F I 32 mm Septal Yes Yes 45 mmHg Aortic and septum

U Streptococcus viridans Yes No 2006 Pachirat et al. (w33)

73 43 M I 18 mm Septal Yes Yes 64 mmHg Mitral Suboptimal oral health

Streptococcus viridans Yes No 2006 Louahabi et al. (w34)

74 53 M U U U U No Mitral U Staphylococcus hominis No No 2007 Cunha et al (w35)

75 75 F II U Septal Yes Yes 50 mmHg Mitral and septum

Septal ablation U No Yes 2008 Zemanek et al (w36)

76 52 F U 14 mm U U No 20.4 mmHg Aortic and Mitral

U Streptococcus viridans Yes No 2009 Yuan et al. (w37)

77 74 F II U U U Yes Mitral U Candida kefyr No No 2010 Chopra et al. (w38)

78 75 F IV U Septal U Yes 80 mmHg Mitral and septum

Septal ablation U No Yes 2010 Curiel Balsera et al. (w39)

79 31 M I U Septal U Yes Septum and LVOT

IV drug abuse Staphylococcus aureus No Yes 2010 Fyfe et al. (w40)

80 52 M III 16 mm Septal Yes Yes 108 mmHg Septum Dental abscess and septal ablation

Staphylococcus aureus No No 2011 Liang et al. (w41)

81 59 M I U U U Yes 35 mmHg Mitral Dental procedure

Actinobacillus endocarditis Yes No 2012 Jorge et al. (w42)

82 62 M I 18 mm Concentric Yes Yes 58 mmHg Aortic and Mitral

IV catheterization

Negative Yes 2012 Katayama el al. (w43)

83 17 F I 22 mm Septal U No 100 mmHg Aortic Dental procedure

Streptococcus sanguis-gordonii

No No 2013 Noel et al. (w44)

84 37 F U 17 mm Septal Yes Yes 130 mmHg Mitral Dental procedure

Negative No Yes 2013 Guler et al. (w45)

IV: intravenous. LVOT: Left ventricular outflow tract. M: Male. F: Female. U: Unknown.8788

Table S3: Baseline characteristics of patients with non-device infective endocarditis (n=1807)

Variable N= 1807Patient age, IQR (years) 68 (56 - 76)Male sex, n (%) 1213 (67.1)ComorbiditiesAge adjusted Charlson comorbidity score, mean (SD)

4.54 (2,6)

Chronic renal impairment, n (%) 441 (24.4) Diabetes mellitus, n (%) 479 (26.5) Cancer, n (%) 298 (16.5) Neurological disease, n (%) 120 (6.6)Predisposing conditions, n (%) Pre-existing valve disease 831 (46.0) Congenital cardiac disease 103 (5.7) Previous endocarditis 144 (8.0) Intravenous drug abuse 55 (3.0)Echocardiography performed, n (%) TTE 1685 (93.2) TEE 1373 (76.0)Site of infection, n (%) Aortic 943 (52.3) Mitral 885 (49) Pulmonary 28 (1.5) Tricuspid 97 (5.4) Native 1246 (69.0) Prosthetic 559 (31)

IQR: Interquartile range; SD: Standard deviation; TTE: Transthoracic echocardiogram; TEE: Transesophageal echocardiography.

89909192

93949596

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